This is the second revision of an application (1 R01 NS056397), "Epidemiologic Study of Brain Vitamin E, Diet and Age-Related Neurologic Diseases", which was not funded. This application proposes to use data from an existing longitudinal clinical-pathologic study, the Religious Orders study, to analyze biochemical levels of the various forms of vitamin E in post-mortem brain tissue and cerebrospinal fluid in 450 deceased participants as well as selected markers of neuropathology and neural reserve, oxidation, inflammation, and insulin activity, and to collect prospectively annual dietary exposure data on the entire cohort of 800 participants. The Religious Orders Study will provide at no cost to the proposed study, data on all non-dietary risk factors, all clinical outcome data on neurological diseases and cognitive and motor function, and most data on post-mortem neuropathology of brain tissue. Recent studies by this group and others suggest that high-dose a-tocopherol, which is currently being tested in clinical trials, may not be the effective therapeutic agent. If funded, the proposed study will have the unprecedented ability to relate brain levels of the various forms of vitamin E to clinical- pathologic outcomes relevant to Alzheimer's disease (AD) and parkinsonian signs as well as to dietary exposures. The proposed multidisciplinary team conducted a pilot study that suggests brain levels of both gamma and alpha tocopherols are inversely related with AD neuropathology and severity of parkinsonian signs, and positively associated with semantic memory. Substantiation of these associations in the entire cohort would be of the utmost importance to the public health, especially given the debilitating and incurable nature of these diseases, and their high occurrence among the fastest growing age group in the US population. Principal Investigator/Program Director (Last, First, Middle): Morris, Martha Clare This is the second revised R01 application to investigate the relations of tocopherols in the brain to age-related neurological diseases and to dietary tocopherols in an existing longitudinal clinical-pathologic study, the Religious Orders Study. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page